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Joe Spano was a member of the San Francisco improv group The Wing, and in college debuted as Paris in a production of Romeo and Juliet in 1967. In 1968, he helped found the Berkeley Repertory Theatre, appearing in its first production, and stayed with the company for 10 years. He moved to Hollywood in the late 1970s, landing guest shots on TV and bit roles in American Graffiti (1973) and The Enforcer (1976/I).

In Hill Street Blues he played Henry Goldblume during the entire seven-year run of the series, first as a detective sergeant, later as a lieutenant. Goldblume was one of Hill Street Precinct Captain Frank Furillo's trusted junior officers, serving at times as a hostage negotiator and gangs relations officer. The character was sympathetic to crime victims, sometimes coming in conflict with his duties as a police officer. Spano was one of many actors appearing through each episode, which typically had several interwoven story lines.

Spano has been a recurring character in NCIS since its premiere episode, "Yankee White", playing FBI Special Agent Tobias Fornell, the FBI counterpart to NCIS Special Agent Leroy Jethro Gibbs, portrayed by Mark Harmon. In Season 15, Fornell is no longer with the FBI, but is a private investigator. The on-screen rapport between the two actors has made Spano much more visible to viewers than his number of actual screen appearances would suggest. Spano is best known for straight dramatic roles but, in NCIS, has adapted to the comedic/drama style of the show. Spano's character, Fornell, holds rank in the FBI equivalent to that held by the NCIS main character, Gibbs. Thus Spano is given key lines and comic moments as a foil for Gibbs and, in some episodes, equal screentime with the main lead. The two characters usually address each other by their first names.

Two episodes have used the Fornells' personal life as the main crux of an NCIS episode: one where Fornell's daughter is imperiled and another where Fornell's career is imperiled. In each episode, it is the friendship between Gibbs and Fornell which is invoked in order to involve NCIS in the resolution of an FBI agent's crisis. Further indicating his status on the show, Spano's Fornell was written into the Gibbs backstory, by having Fornell been married to Gibbs' first ex-wife, linking their private lives as well as their professional lives and further establishing their equivalence of status. Spano's character has also been involved in operations run by other agencies, including both Homeland Security and the CIA, as the liaison between those agencies and NCIS.

Notable episodes of NCIS, featuring Spano in a prime role, include the Episode 1, Season 1 "Yankee White", Episode 2 of Season 4 "Escaped", as well as episodes titled "Seadog", "Enigma", "Reveille", "The Boneyard", "Conspiracy Theory", "Twilight", "Kill Ari: Part 2", "Under Covers", "Frame up", "Smoked", "Brothers in Arms" and "Angel of Death", all of which are available for searching on the NCIS pages. Spano continued to appear in season 5 of NCIS, starting with "Identity Crisis" about an FBI operation gone wrong and "Internal Affairs" when NCIS is being investigated for murder. In season 6, he appears in the episodes "Nine Lives" and "Semper Fidelis". In season 7, he appears in the episodes "Jack-Knife" and "Moonlighting". He continues to appear in the following seasons as well, in the episodes "Short Fuse" and "Tell-All" (both season 8), "Devil's Triangle", and "Life Before His Eyes" (both season 9), "Extreme Prejudice", "Devil's Trifecta", "Damned If You Do" (all season 10), and "Whiskey Tango Foxtrot", "Past, Present, and Future", "Devil's Triad", "Crescent City (Part I)", and "Crescent City (Part II)" (all season 11), "Cabin Fever" (season 12), "Dead Letter" and "Family First" (season 13), "Privleged Information" (season 14), and "Burden of Proof", "Keep Your Friends Close" (Fornell is no longer with the FBI as of this episode) and "Keep Your Enemies Closer" [3] (all season 15).

Spano was born in San Francisco, California, the son of Virginia Jean (née Carpenter) and Vincent Dante Spano, a physician.[4] He graduated from Archbishop Riordan High School in 1963, and he is an honorary member of the House of Russi. Spano and his wife Joan Zerrien, a therapist, were married in 1980. They have two adopted daughters.